ASN's Mission

ASN leads the fight to prevent, treat, and cure kidney diseases throughout the world by educating health professionals and scientists, advancing research and innovation, communicating new knowledge, and advocating for the highest quality care for patients.

learn more

Contact ASN

1401 H St, NW, Ste 900, Washington, DC 20005

email@asn-online.org

202-640-4660

The Latest on Twitter

Kidney Week

Abstract: PO1549

Suppressed Autophagic Flux in the Heart in a Hypomorphic Pkd1 Mouse Model of ADPKD

Session Information

Category: Genetic Diseases of the Kidneys

  • 1001 Genetic Diseases of the Kidneys: Cystic

Authors

  • Atwood, Daniel, Univ Colorado, Aurora, Colorado, United States
  • Brown, Carolyn Nicole, Univ Colorado, Aurora, Colorado, United States
  • Hopp, Katharina, Univ Colorado, Aurora, Colorado, United States
  • Edelstein, Charles L., Univ Colorado, Aurora, Colorado, United States
Background

Heart disease is largely unexplored in mouse models of ADPKD. The aim of the study was to determine mTOR signaling and autophagy in the heart in Pkd1RC/RC (RC) mice

Methods

Proteins were determined by immunoblot analysis. Mice were treated with autophagy inducers 2-deoxyglucose (2-DG) or Tat-Beclin1 peptide (Tat).

Results

There was increased heart weight/body weight ratio (HW/BW) in 180 d old RC mice. In 70 day old RC hearts, there was no increase in mTOR but a large increase in p-AMPKThr172, a known autophagy inducer. In 150 day old RC hearts, there was an increase in p-S6, p-AktThr308, p-GSK3β, p-AMPK, p-Beclin, an autophagy regulator and activating molecule in Beclin-1-regulated autophagy (AMBRA1). There was suppressed autophagic flux (lack of an increase in LC3-II, a marker of autophagosomes, with the lysosomal inhibitor bafilomycin-Baf), in 70 and 150 d old RC hearts compared to an increase in wild type (WT) hearts. In 120 d old RC hearts there was no increase in proliferation (PCNA) or apoptosis (TUNEL). Both 2-DG and Tat treatment increased heart weight and had no effect on kidney weight

Conclusion

There was a large increase in p-AMPK and suppressed autophagy in RC hearts. Unexpectedly, autophagy inducers increased heart weight

 Age (days)WTRC
HW/BW (%)1500.490.52
HW/BW (%)1800.570.71***
Densitometry   
p-S61200.71.3*
p-Akt1200.61.5*
p-GSK3B1201.11.4*
p-AMPK70/1200.51.5**
p-Beclin1200.30.7*
AMBRA1200.30.8**
  WT VehWT Baf
LC3-II700.91.7*
LC3-II1200.61.3*
  RC VehRC Baf
LC3-II700.20.3
LC3-II1200.90.9
HW/BW (%) RCRC+Tx
2-DG150-3500.540.59
Tat70-1200.530.62*
2K/BW (%)   
2-DG150-3502.82.7
Tat70-1202.42.3

*P<0.05, **P<0.01. ***P<0.001

Funding

  • Veterans Affairs Support